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Background: The CpG island methylator phenotype (CIMP or CIMP-high) with extensive promoter methylation is a distinct phenotype in colorectal cancer. However, a choice of markers for CIMP has been controversial. A recent extensive investigation has selected five methylation markers (CACNA1G, IGF2,NEUROG1, RUNX3 and SOCS1) as surrogate markers for epigenomic aberrations in tumor. The use of these markers as a CIMP-specific panel needs to be validated by a large independent dataset.

Design: We collected 920 colorectal cancers from two large prospective cohort studies. Utilizing MethyLight assays, we quantified DNA methylation in eight CIMP-specific markers {CACNA1G, IGF2, NEUROG1, RUNX3, SOCS1, plus CDKN2A (p16), CRABP1 and MLH1}. We determined microsatellite instability (MSI) status and sequenced KRAS and BRAF.

Results: A CIMP-high cutoff was set at ≥6/8 or ≥5/8 methylated promoters, based on BRAF and KRAS mutation frequency spectra in MSI-high and microsatellite stable (MSS) tumors. Table shows sensitivity, specificity and concordance rates of a single marker-based CIMP diagnosis against the 8-marker CIMP panel. All but two very specific markers [MLH1 (98% specific) and SOCS1 (93% specific)] demonstrated ≥87% sensitivities and ≥80% specificities. Based on the data, the eight markers were ranked in order as: RUNX3, CACNA1G, IGF2, MLH1, NEUROG1, CRABP1, SOCS1 and CDKN2A. A panel of markers including at least RUNX3, CACNA1G, IGF2 and MLH1 could serve as a sensitive and specific marker panel for CIMP-high.

Conclusion: Our results indicate overall good concordance in methylation patterns and good performance of all of the 8 markers.

Table. Sensitivity & Specificity of Each Marker for Diagnosis of CIMP-High in 920 Colorectal Cancers

Sensitivity = “(the number of CIMP-high cases positive for a given marker) / (the number of all CIMP-high cases)”. Specificity = “(the number of CIMP-low/0 cases negative for a given marker) / (the number of all CIMP-low/0 cases)”.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA